The neurotoxicity of misonidazole: potential modifying role of phenytoin sodium and dexamethasone

Th, Wasserman; Tl, Phillips; G, Van Raalte; Urtasun, Raul C.; Partington, J; Koziol, Deloris E.; Jg, Schwade; Gangji, Diamon; Jm, Strong

doi:10.1259/0007-1285-53-626-172

Cited by 52 publications

(9 citation statements)

References 4 publications

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“…Induction of hepatic enzymes by phenytoin and phenobarbital shorten the t'/2 of misonidazole by approximately 30% (Moore et al 1982;Wasserman et al 1980). The mean CL of misonidazole was increased by 42% with phenytoin and 31 % by phenobarbital following a I-week course of therapy.…”

Section: Misonidazolementioning

confidence: 98%

Clinical Pharmacokinetics of Metronidazole and Other Nitroimidazole Anti-Infectives

Lau

Lam

Piscitelli

et al. 1992

Clinical Pharmacokinetics

184

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Metronidazole was first introduced for the treatment of trichomoniasis. Its therapeutic use has subsequently been expanded to include amoebiasis, giardiasis and, more recently, anaerobic infections. Most of the early pharmacokinetic studies employed nonspecific assays such as microbiological and chemical assays. These assays were not able to differentiate the parent drug from the metabolites or other interfering substances. Pharmacokinetic data obtained through the use of specific chromatographic techniques provide the basis for this review of recent pharmacokinetic findings concerning metronidazole and other nitroimidazole antibiotics. When given intravenously or orally at usual recommended doses, metronidazole attains concentrations well above the minimum inhibitory concentrations for most susceptible micro-organisms. The drug has an oral bioavailability approaching 100%. Rectal and vaginal administration results in a smaller amount of drug absorption and lower serum concentrations. Metronidazole has limited plasma protein binding but can attain very favourable tissue distribution, including into the central nervous system. The drug is extensively metabolised by the liver to form 2 primary oxidative metabolites: the hydroxy and acetic acid metabolites. The kidney is responsible for the elimination of only a small amount of the parent drug; however, normal excretion of the 2 metabolites is dependent on the integrity of kidney function. The metabolism of metronidazole was found to vary among patient groups. Preterm and term infants have lower total body clearance (CL) and prolonged elimination half-lives. However, children older than 4 years old were observed to have pharmacokinetic parameters similar to those in adults. Reduced CL was also observed in children who are malnourished. Elderly patients have reduced renal excretion of both the parent drug and hydroxy metabolite. Pharmacokinetic parameters in pregnant patients were not significantly different from those in nonpregnant women; however, the drug is distributed into breastmilk and the infant will be exposed to the drug through the nursing mother. Patients undergoing gastrointestinal surgery or having enteric diseases and those who are hospitalised or critically ill also have altered pharmacokinetics. Metabolism of the drug is reduced in patients with liver dysfunction, giving delayed production of metabolites. In contrast, renal failure has little effect on the elimination of the parent drug, but affects the excretion of the metabolites more significantly. Haemodialysis was found to remove a substantial amount of the metronidazole while the effect of peritoneal dialysis was more limited. Energy and protein deficient diets as well as occupational exposure to gasoline did not alter metronidazole pharmacokinetics. However, the effect of alcohol consumption on metronidazole CL requires further study.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Misonidazolementioning

confidence: 98%

Clinical Pharmacokinetics of Metronidazole and Other Nitroimidazole Anti-Infectives

Lau

Lam

Piscitelli

et al. 1992

Clinical Pharmacokinetics

184

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“…There is some evidence that dexamethasone, an anti-inflammatory steroid, protects against Misoinduced neurotoxicity in man (15).…”

Section: Discussionmentioning

confidence: 99%

Renal elimination of the hypoxic cell radiosensitizer misonidazole in wistar rats: influence of some drugs on its excretion

Akel¹,

Canal

Soula

1985

European Journal of Drug Metabolism and Pharmacokinetics

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The hypoxic cell radiosensitizing drug, misonidazole (Miso) (Ro 07-0582) and its demethylated metabolite were administered to Wistar rats at different dose levels to examine their renal elimination. The data were consistent with a model in which Miso is eliminated mainly after biotransformation into desmethylmisonidazole (Demiso) which is eliminated according to its renal clearance. The study of Miso renal elimination process shows a tubular reabsorption. So we analyzed the interaction of various drugs on urinary 24 hours elimination of this radiosensitizer. Following results were observed: Furosemide and acetazolamide do not change the rate of renal elimination of the drug; Soludactone increases the elimination level of unmetabolized Miso (p less than 0.01); Under probenecid treatment, the elimination of Miso and its O-demethylated derivative are increased; On the other hand, after a pretreatment with phenobarbital, the urinary level of desmethylmisonidazole is strongly increased (p less than 0.001).

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“…In mice, phenytoin and phenobarbitone have been shown to achieve this by increasing the rate of oxidative demethylation in the liver (Workman, 1979), Dexamethasone phosphate, though not influencing the concentration of MISO in the blood of mice, has been observed to reduce the concentration in the brain, possibly by reducing the cerebrovascular permeability and/or blood flow (Workman, 1980a). Fortuitously, all these drugs have been used as either anti-convulsants or antiinflammatory agents in a number of clinical trials with MISO of patients with gliomas (Bleehen, 1980;Wasserman et al, 1980). We report here the influence of these drugs (i.e.…”

mentioning

confidence: 99%

The effect of phenytoin, phenobarbitone, dexamethasone and flurbiprofen on misonidazole neurotoxicity in mice

Clarke¹,

Dawson²

1984

Br J Cancer

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Summary Using a quantitative cytochemical technique for measuring ,B-glucuronidase activity in the peripheral nerves of mice, we have investigated the effectiveness of four potential adjuncts for reducing the dose limiting neurotoxicity of misonidazole (MISO) in the clinic.Under the conditions used, the most effective adjunct was the steroid anti-inflammatory agent dexamethasone. When given over the week previous to MISO treatment, this agent almost completely eliminated the MISO neurotoxicity as determined at week 4 after commencement of MISO dosing. The second most effective adjunct was phenytoin, the third flurbiprofen and the last adjunct, phenobarbitone, was ineffective.Dexamethasone, phenytoin and phenobarbitone all reduced the clearance half-life of MISO and hence the drug exposure dose calculated as the area under the curve of MISO tissue concentration against time. However, no correlation was evident with these parameters and MISO neurotoxicity in the mouse.Dexamethasone, whilst affording protection against MISO toxicity, did not alter the radiosensitivity of the anaplastic MT tumour.

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The neurotoxicity of misonidazole: potential modifying role of phenytoin sodium and dexamethasone

Cited by 52 publications

References 4 publications

Clinical Pharmacokinetics of Metronidazole and Other Nitroimidazole Anti-Infectives

Clinical Pharmacokinetics of Metronidazole and Other Nitroimidazole Anti-Infectives

Renal elimination of the hypoxic cell radiosensitizer misonidazole in wistar rats: influence of some drugs on its excretion

The effect of phenytoin, phenobarbitone, dexamethasone and flurbiprofen on misonidazole neurotoxicity in mice

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